Method for the preparation of citalopram

ABSTRACT

Disclosed is a method for the preparation of citalopram comprising conversion of a compound of Formula VIII  
                 
 
     wherein Z is halogen, to a compound of Formula IV  
                 
 
     followed by conversion of the compound of Formula IV into citalopram. Methods for the preparation of the compound of Formula IV are also disclosed.

[0001] The present invention relates to a method for the preparation ofthe well-known antidepressant drug citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,methods for the preparation of intermediates used in the preparation ofcitalopram, and methods for conversion of said intermediates intocitalopram.

BACKGROUND OF THE INVENTION

[0002] Citalopram is a well-known antidepressant drug that has now beenon the market for some years and has the following structure:

[0003] It is a selective, centrally acting serotonin(5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly havingantidepressant activities. The antidepressant activity of the compoundhas been reported in several publications, eg. J. Hyttel Prog.Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6, 277-295 and A. GravemActa Psychiatr. Scand. 1987, 75, 478-486. The compound has further beendisclosed to show effects in the treatment of dementia andcerebrovascular disorders, EP-A 474580.

[0004] Citalopram was first disclosed in DE 2,657,013, corresponding toU.S. Pat. No. 4,136,193. This patent publication describes thepreparation of citalopram by one method and outlines a further method,which may be used for preparing citalopram.

[0005] According to the process described, the corresponding1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is reactedwith 3-(N,N-dimethylamino)propyl-chloride in the presence ofmethylsulfinylmethide as condensing agent. The starting material wasprepared from the corresponding 5-bromo derivative by reaction withcuprous cyanide.

[0006] According to the method, which is only outlined in general terms,citalopram may be obtained by ring closure of the compound:

[0007] in the presence of a dehydrating agent and subsequent exchange ofthe 5-bromo group with cuprous cyanide. The starting material of FormulaII is obtained from 5-bromophthalide by two successive Grignardreactions, i.e. with 4-fluorophenyl magnesium chloride andN,N-dimethylaminopropyl magnesium chloride, respectively.

[0008] A new and surprising method and an intermediate for thepreparation of citalopram were described in U.S. Pat. No 4,650,884,according to which an intermediate of Formula III

[0009] is subjected to a ring closure reaction by dehydration withstrong sulfuric acid in order to obtain citalopram. The intermediate ofFormula III was prepared from 5-cyanophthalide by two successiveGrignard reactions, i.e. with 4-fluorophenyl magnesium halogenide andN,N-dimethylaminopropyl magnesium halogenide, respectively.

[0010] Further processes are disclosed in international patentapplication Nos. WO 98019511, WO 98019512 and WO 98019513. WO 98019512and WO 98019513 relate to methods wherein a 5-amino-, 5-alkoxycarbonyl-or 5-(sec. aminocarbonyl)phthalide is subjected to two successiveGrignard reactions, ring closure and conversion of the resulting1,3-dihydroisobenzofuran derivative to the corresponding 5-cyanocompound, i.e. citalopram. International patent application No. WO98019511 discloses a process for the manufacture of citalopram wherein a(4-substituted-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compoundis subjected to ring closure and the resulting 5-substituted1-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to thecorresponding 5-cyano derivative, which is alkylated with a(3-dimethylamino)propylhalogenide in order to obtain citalopram.

[0011] Finally, methods of preparing the individual enantiomers ofcitalopram are disclosed in U.S. Pat. No 4,943,590 from which it alsoappears that the ring closure of the intermediate of Formula III may becarried out via a labile ester with a base.

[0012] It has now, surprisingly, been found that citalopram may bemanufactured by a novel favourable and safe procedure using convenientstarting materials.

SUMMARY OF THE INVENTION

[0013] Accordingly, the present invention relates to a novel method forthe preparation of citalopram having the Formula I

[0014] comprising:

[0015] conversion of a compound of Formula VIII

[0016] wherein Z is halogen,

[0017] to a compound of Formula IV

[0018] followed by conversion of the compound of Formula IV intocitalopram.

[0019] In particular the invention relates to such a method comprising:

[0020] i) reaction of the compound of Formula IV with a dehydratingagent and a sulfonamide of the Formula H₂N—SO₂—R wherein R is:

[0021] a) An optionally substituted NH₂, or C₁₋₆ alkyloxy,

[0022] b) aryloxy or heteroaryloxy optionally substituted with halogen,C₁₋₄-alkyl, cyano, hydroxy, C₁₋₄-alkoxy, trifluoromethyl, nitro, amino,C₁₋₄-alkylamino or di-C₁₋₄-alkylamino, or

[0023] c) aryl or heteroaryl optionally substituted with halogen,C₁₋₄-alkyl, cyano, hydroxy, C₁₋₄-alkoxy, trifluoromethyl, nitro, amino,Cl₄-alkylamino or di-C₁₋₄-alkylamino;

[0024] or

[0025] ii) conversion of the compound of Formula IV to the correspondingamide of Formula V

[0026] in which R¹ and R² are independently hydrogen, C₁₋₆ alkyl,C₁₋₆-alkyl substituted with one or more substituents selected from thegroup comprising aryl and heteroaryl, hydroxy, C₁₋₆-alkoxy, aryloxy,heteroaryloxy, aryl-C₁₋₆-alkoxy, or trisubstituted silyl wherein thesubstituents are independently C₁₋₆ alkyl, aryl, heteroaryl oraryl-C₁₋₆-alkyl and then reacting the amide of Formula V with adehydrating agent thereby obtaining citalopram as the base or apharmaceutically acceptable salt thereof.

[0027] The conversion of the 5-carboxy derivative of Formula IV to theamide of Formula V may be carried out via activated acid derivative ofFormula VI:

[0028] wherein R³ is halogen, C₁₋₆alkoxy,aryloxy, heteroaryloxy,aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, alkylcarbonate, arylcarbonate,alkylcarbamate, arylcarbamate, alkylthiocarbonate, arylthiocarbonate,alkylthiocarbamate, arylthiocarbamate, alkylacyloxy, arylacyloxy,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

[0029] In another aspect, the invention relates to methods for thepreparation of the intermediate of Formula IV comprising conversion of acompound of Formula VIII, wherein Z is halogen to compound of FormulaIV.

[0030] In yet another aspect, the invention relates to methods for thepreparation of the intermediate of Formula VII

[0031] wherein X is selected from halide, CN, OR⁵ or SR⁶ where R⁵ and R⁶are independently selected from C₁₋₆ alkyl, aryl, heteroaryl or benzyland each of these C₁₋₆ alkyl, aryl, heteroaryl or benzyl groups areunsubstituted or substituted with halogen, C₁₋₄ alkyl, cyano, hydroxy,C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄alkylamino, NR⁷R⁸ where R⁷ and R⁸ are independently selected fromhydrogen, C₁₋₆ alkyl, aryl, heteroaryl or benzyl and each of these C₁₋₆alkyl, aryl, heteroaryl or benzyl groups are unsubstituted orsubstituted with halogen, C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkoxy,trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄ alkylamino;

[0032] Y is O, S, or NR⁹ where R⁹ is selected from hydrogen, C₁₋₆ alkyl,aryl, heteroaryl or benzyl and each of these C₁₋₆ alkyl, aryl,heteroaryl or benzyl groups are unsubstituted or substituted withhalogen, C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkoxy, trifluoromethyl,nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄-alkylamino;

[0033] comprising

[0034] conversion of a compound of Formula VIII

[0035] wherein Z is halogen,

[0036] to a compound of Formula VII.

[0037] In yet another aspect, the present invention relates to anantidepressant pharmaceutical composition comprising citalopram as thebase or any convenient salt thereof manufactured by the process of theinvention.

[0038] Throughout the specification and claims, the term ‘dehydratingagent’ refers to any suitable dehydrating agent, and a person skilled inthe art may easily determine the optimal agent. Examples of suitabledehydrating agents are SOCl₂, POCl₃, PCl₅, SOBr₂, POBr₃, PBr₅, SOI₂,POI₃, PI₅, P₄O₁₀, oxalylchloride, carbonyldiimidazole and Vilsmeierreagents. Preferably a chloro-containing agent, most preferably SOCl₂ orPOCl₃, is used. Vilsmeier reagents are reagents formed by mixing ofN,N-dimethylformamide (DMF) and dehydrating agents, examples of whichare DMF/SOCl₂ and DMF/POCl₃.

[0039] Throughout the specification and claims, C₁₋₆ alkyl refers to abranched or unbranched alkyl group having from one to six carbon atomsinclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.Similarly, C₁₋₄ alkyl refers to such a group having from one to fourcarbon atoms inclusive and C₁₋₆ alkoxy, C₁₋₄ alkoxy and C₁₋₄ alkylaminedesignate such groups wherein the alkyl moity is as defined.

[0040] Halogen means fluorine, chlorine, bromine or iodine.

[0041] In the method i) of the invention, one possible but non-limitingmechanism of the reaction is that the 5-carboxy compound of Formula IVreacts with the dehydration agent in order to form a correspondingactivated derivative, which then reacts with the sulfonamide, H₂N—SO₂—R,thereby forming citalopram. During the latter reaction, a catalyticamount of an acid may be necessary.

[0042] The sulfonamide, H₂N—SO₂—R, used in the process is preferablysulfamide, NH₂—SO₂—NH₂.

[0043] The optionally substituted NH₂ used in the process is preferablytert-butylamine.

[0044] The reactions with dehydration agents in the method of theinvention are carried out neat or in a suitable solvent, such assulfolane or acetonitrile. When a solvent is used in the dehydrationreaction of ii), a catalytic amount of N,N-dimethylformamide may beneeded.

[0045] In preferred embodiments of the invention, the methods forpreparation of citalopram and/or the compounds of Formula IV or FormulaVII comprises:

[0046] a) Reaction of the 5-halo analogue of Formula VIII

[0047] wherein Z is halogen,

[0048] with Mg or an organolithium compound, e.g. n-BuLi, or with anorganometallic complex composed of Mg and/or Mn and/or Li and alkyl oraryl groups and subsequently with CO₂, CS₂ or a compound of the FormulaIX

[0049] wherein A and X are independently selected from halide, CN, OR⁵or SR⁶ where R⁵ and R⁶ are independently selected from C₁₋₆ alkyl, aryl,heteroaryl or benzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl orbenzyl groups are unsubstituted or substituted with halogen, C₁₋₄ alkyl,cyano, hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄alkylamino or di-C₁₋₄ alkylamino, NR⁷R⁸ where R⁷ and R⁸ areindependently selected from hydrogen, C₁₋₆ alkyl, aryl, heteroaryl orbenzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl or benzyl groupsare unsubstituted or substituted with halogen, C₁₋₄ alkyl, cyano,hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄ alkylamino ordi-C₁₋₄ alkylamino; Y is O, S, or NR⁹ where R⁹ is selected fromhydrogen, C₁₋₆ alkyl, aryl, heteroaryl or benzyl and each of these C₁₋₆alkyl, aryl, heteroaryl or benzyl groups are unsubstituted orsubstituted with halogen, C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkoxy,trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄ alkylamino;

[0050] and in the methods for manufacture of citalopram or compounds ofFormula IV followed by reaction with water, a hydroxide such as NaOH, oran aqueous solution of an acid;

[0051] b) coupling of a compound of Formula VIII

[0052] wherein Z is Br or I with an optionally substituted vinyl oracetylenic group in the presence of a metal catalyst, such as a nickelor palladium based catalyst, followed by oxidation of the vinyl oracetylenic group to carboxy thereby obtaining the compound of FormulaIV;

[0053] In method a), examples of organometallic complexes aretrialkylmagnesates of the Formula (R⁴)₃MgLi, trialkylmangenates of theFormula (R⁴)₃MnLi and mixed magnesium and mangenate complexes of theFormula (R⁴)₃MnMgBr, wherein R⁴ designates C₁₋₆-alkyl or aryl groupsthat may be identical or different. Trialkylmagnesate may be prepared insitu from a Grignard reagent R⁴MgX (X is halogen) and an organolithium,e.g. n-butyllithium. Trialkylmangenate may be generated in situ fromMnCl₂ and an organolithium e.g. n-butyllithium. (R⁴)₃MnMgBr may beprepared from a Grignard reagent R⁴MgX and MnCl₂.. The starting 5-bromocompound of Formula VIII may be obtained as described in U.S. Pat. No.4,136,193.

[0054] In method a), examples of starting materials of Formula IX are:ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, vinylchloroformate, isobutyl chloroformate, ethyl chlorothiolformate, methylcyanoformate, carbonyldiimidazole and diethyl carbonate. The startingmaterials of Formula IX are commercially available or may be prepared byliterature methods.

[0055] In method b), the nickel based catalyst may be any suitable Ni(0)or Ni(II) containing complex which acts as a catalyst, such as Ni(PPh₃)₃and (σ-aryl)-Ni(PPh₃)₂Cl, and the palladium based catalyst may be anysuitable Pd(0) or Pd(II) containing catalyst, such as Pd(PPh₃)₄,Pd₂(dba)₃ and Pd(PPh)₂Cl₂. The oxidation agent may be any suitableagent, such as a peroxide in the presence of a ruthenium catalyst. Thestarting compounds wherein B is a triflate group may be obtained asdescribed in WO 0013648. Examples of the vinyl or acetylenic groupscoupled with the compound of Formula VIII are methyl acrylate,1-bromobut-1-ene, propyne, trimethyl(prop-1-enyl)stannane,E-1-hexenylboronic acid and prop-1-enyl trifluoromethylsulfonate.

[0056] The compound of Formula I may be used as the free base or as apharmaceutically acceptable acid addition salt thereof. As acid additionsalts, such salts formed with organic or inorganic acids may be used.Exemplary of such organic salts are those with maleic, fumaric, benzoic,ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids.

[0057] The acid addition salts of the compounds may be prepared bymethods known in the art. The base is reacted with either the calculatedamount of acid in a water miscible solvent, such as acetone or ethanol,with subsequent isolation of the salt by concentration and cooling, orwith an excess of the acid in a water immiscible solvent, such asdiethylether, ethylacetate or dichloromethane, with the salt separatingspontaneously.

[0058] The pharmaceutical compositions of the invention may beadministered in any suitable way and in any suitable form, for exampleorally in the form of tablets, capsules, powders or syrups, orparenterally in the form of usual sterile solutions for injection.

[0059] The pharmaceutical Formulations of the invention may be preparedby conventional methods in the art. For example, tablets may be preparedby mixing the active ingredient with ordinary adjuvants and/or diluentsand subsequently compressing the mixture in a conventional tablettingmaschine. Examples of adjuvants or diluents comprise: Corn starch,potato starch, talcum, magnesium stearate, gelatine, lactose, gums, andthe like. Any other adjuvant or additive colourings, aroma,preservatives etc. may be used provided that they are compatible withthe active ingredients.

[0060] Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to thedesired volume, sterilising the solution and filling it in suitableampoules or vials. Any suitable additive conventionally used in the artmay be added, such as tonicity agents, preservatives, antioxidants, etc.

Examples

[0061] The invention is further illustrated by the following examples,which should not be construed as limiting the scope of the invention.

Example 1

[0062]5-Carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran.

[0063] Method a)—Mg.

[0064] A solution of1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran-5-ylmagnesium bromide in dry THF (90 mL) (prepared by ordinary methods from5-bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran(9 g, 0.024 mole) and magnesium (0.73 g, 0.03 mole)) was added to drysolid CO₂ (50 g). After addition, the mixture was left at roomtemperature for 16 hours.

[0065] The volatile materials were removed in vacuo and the residue wastaken up in water (100 mL). pH was adjusted to 5.5 by adding HCl(aqueous, 4 N). The aqueous phase was extracted with toluene (100 mL).

[0066] The toluene was removed in vacuo and the title compound wasobtained as oil. Yield 6 grams.

[0067] Method a)—n-BuLi

[0068] To a solution of5-bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran(9 g, 0.024 mole) in tert.butyl methyl ether (150 mL) was added n-BuLi(1.6 M in hexanes, 40 mL) at −78° C. to 65° C. The temperature of thesolution was allowed to raise to −30° C. over a period of 2 hours. Thereaction mixture was added to dry solid CO₂ (50 g). After addition, themixture was left at room temperature for 16 hours. The volatilematerials were removed in vacuo and the residue was taken up in water(100 mL). pH was adjusted to 5.5 by adding HCl (aqueous, 4 N). Theaqueous phase was extracted with toluene (100 mL). The toluene wasremoved in vacuo and the title compound was obtained as an oil. Yield7.5 grams.

[0069] Method a)—trialkylmagnesate

[0070] n-BuLi (20 mL, 1.6 M in hexane) was added to a solution ofisopropylmagnesium chloride (8.0 mL, 2 M in diethylether) in THF (25 mL)at 0 ° C. The resulting mixture was stirred at 0° C. for 1 h, thencooled to −78° C. and a solution of5-bromo-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran(5.0 g, 13.0 mmol) in THF (25 mL) was added. The mixture was allowed towarm to −10 ° C. during 1 h, then cooled again to −78 ° C., and CO₂ (5.7g, 130 mmol) was added. The mixture was allowed to warm to roomtemperature, and then evaporated. Ion exchange chromatography of theresidue (Dowex®-50, acidic form) eluting with 1 M NH₃ afforded theproduct as a thick oil.

Example 2

[0071]5-Cyano-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran.(Citalopram, free base)

[0072]5-Carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran(5 g, 0.015 mole) and sulfamide (1.65 g, 0.017 mole) were dissolved insulfolane (15 mL). Thionylchloride (2.25 g, 0.019 mole) was added atroom temperature and the temperature of the reaction mixture was raisedto 130° C. for 2 hours. The reaction mixture was allowed to cool to 75°C. and water (25 mL) was added. The temperature was held at 75° C. for15 min, and then the reaction mixture was cooled to room temperature. pHwas ajusted to 9 with ammonium hydroxide and then n-heptane (75 mL) wasadded. The temperature was raised to 70° C. and the hot n-heptane layerwas isolated from which the title compound crystallised on cooling.Yield 3.77 g. Purity (HPLC peak area)>97%.

1. A method for the preparation of citalopram

comprising conversion of a compound of Formula VIII

wherein Z is halogen, to a compound of formula IV

followed by conversion of the compound of formula IV into citalopram. 2.A method according to claim 1, wherein: i) the compound of Formula IV isreacted with a dehydrating agent and a sulfonamide of the FormulaH₂N—SO₂—R wherein R is: a) an optionally substituted NH₂, or C₁₋₆alkyloxy, b) aryloxy or heteroaryloxy optionally substituted withhalogen, C₁₋₄-alkyl, cyano, hydroxy, C₁₋₄-alkoxy, trifluoromethyl,nitro, amino, C₁₋₄-alkylamino or di-C₁₋₄-alkylamino, or c) aryl orheteroaryl optionally substituted with halogen, C₁₋₄-alkyl, cyano,hydroxy, C₁₋₄-alkoxy, trifluoromethyl, nitro, amino, C₁₋₄-alkylamino ordi-C₁₋₄-alkylamino; or ii) the compound of Formula IV is converted tothe corresponding amide of Formula V

in which R¹ and R² are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsubstituted with one or more substituents selected from the groupconsisting of aryl and heteroaryl, hydroxy, C₁₋₆-alkoxy, aryloxy,aryl-C₁₋₆-alkoxy, or trisubstituted silyl wherein the substituents areindependently C₁₋₆ alkyl, aryl, heteroaryl or aryl-C₁₋₆-alkyl and thenreacting the amide of Formula V with a dehydrating agent therebyobtaining citalopram as the base or a pharmaceutically acceptable saltthereof.
 3. The method according to claim 2, wherein the compound ofFormula IV is reacted with SOCl₂ and sulfamide.
 4. The method of claim3, wherein the reaction is performed in sulfolan.
 5. The method of claim2, wherein the compound of Formula IV is reacted with POCl₃ andtert-butylamine.
 6. The method of claim 1, wherein the compound ofFormula IV is obtained by: i) reacting the compound of Formula VIII

wherein Z is halogen, with Mg or an organolithium compound, or with anorganometallic complex composed of Mg and/or Mn and/or Li and alkyl oraryl groups to achieve a first intermediate; ii) subsequently reactingsaid first intermediate with CO₂, CS₂ or a compound of Formula IX

wherein A and X are independently selected from halide, CN, OR⁵ or SR⁶where R⁵ and R⁶ are independently selected from C₁₋₆ alkyl, aryl,heteroaryl or benzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl orbenzyl groups are unsubstituted or substituted with halogen, C₁₋₄ alkyl,cyano, hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄alkylamino or di-C₁₋₄ alkylamino, NR⁷R⁸ where R⁷ and R⁸ areindependently selected from hydrogen, C₁₋₆ alkyl, aryl, heteroaryl orbenzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl or benzyl groupsare unsubstituted or substituted with halogen, C₁₋₄ alkyl, cyano,hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄ alkylamino ordi-C₁₋₄ alkylamino; Y is O, S, or NR⁹ where R⁹ is selected fromhydrogen, C₁₋₆ alkyl, aryl, heteroaryl or benzyl and each of these C₁₋₆alkyl, aryl, heteroaryl or benzyl groups are unsubstituted orsubstituted with halogen, C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkoxy,trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄ alkylamino; toachieve a second intermediate; iii) and subsequently reacting saidsecond intermediate with water, a hydroxide such as NaOH, or an aqueoussolution of an acid.
 7. The method of claim 1, wherein the compound ofFormula IV is obtained by coupling of a compound of Formula VIII

wherein Z is Br or I with an optionally substituted vinyl or acetylenicgroup in the presence of a metal catalyst, followed by oxidation of thevinyl or acetylenic group to carboxy thereby obtaining the compound ofFormula IV.
 8. A method for the preparation of a compound of Formula IV

comprising conversion of a compound of Formula VIII

wherein Z is halogen, to a compound of Formula IV.
 9. The method ofclaim 8, wherein the compound of Formula IV is obtained by: i) reactingthe compound of Formula VIII

wherein Z is halogen, with Mg or an organolithium compound, or with anorganometallic complex composed of Mg and/or Mn and/or Li and alkyl oraryl groups to achieve a first intermediate; ii) subsequently reactingsaid first intermediate with CO₂, CS₂ or a compound of Formula IX

wherein A and X are independently selected from halide, CN, OR⁵ or SR⁶where R⁵ and R⁶ are independently selected from C₁₋₆ alkyl, aryl,heteroaryl or benzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl orbenzyl groups are unsubstituted or substituted with halogen, C₁₋₄ alkyl,cyano, hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄alkylamino or di-C₁₋₄ alkylamino, NR⁷R⁸ where R⁷ and R⁸ areindependently selected from hydrogen, C₁₋₆ alkyl, aryl, heteroaryl orbenzyl and each of these C₁₋₆alkyl, aryl, heteroaryl or benzyl groupsare unsubstituted or substituted with halogen, C₁₋₄ alkyl, cyano,hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄ alkylamino ordi-C₁₋₄ alkylamino; Y is O, S, or NR⁹ where R⁹ is selected fromhydrogen, C₁₋₆ alkyl, aryl, heteroaryl or benzyl and each of these C₁₋₆alkyl, aryl, heteroaryl or benzyl groups are unsubstituted orsubstituted with halogen, C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkoxy,trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄ alkylamino; toachieve a second intermediate; iii) and subsequently reacting saidsecond intermediate with water, a hydroxide such as NaOH, or an aqueoussolution of an acid.
 10. The method of claim 8, wherein the compound ofFormula IV is obtained by coupling of a compound of Formula VIII

wherein Z is Br or I with an optionally substituted vinyl or acetylenicgroup in the presence of a metal catalyst, followed by oxidation of thevinyl or acetylenic group to carboxy thereby obtaining the compound ofFormula IV.
 11. A method for the preparation of a compound of FormulaVII

wherein X is selected from halide, CN, OR⁵ or SR⁶ where R⁵ and R⁶ areindependently selected from C₁₋₆ alkyl, aryl, heteroaryl or benzyl andeach of these C₁₋₆ alkyl, aryl, heteroaryl or benzyl groups areunsubstituted or substituted with halogen, C₁₋₄ alkyl, cyano, hydroxy,C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄alkylamino, NR⁷R⁸ where R⁷ and R⁸are independently selected fromhydrogen, C₁₋₆ alkyl, aryl, heteroaryl or benzyl and each of these C₁₋₆alkyl, aryl, heteroaryl or benzyl groups are unsubstituted orsubstituted with halogen, C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkoxy,trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄ alkylamino; Yis O, S, or NR⁹ where R⁹ is selected from hydrogen, C₁₋₆ alkyl, aryl,heteroaryl or benzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl orbenzyl groups are unsubstituted or substituted with halogen, C₁₋₄ alkyl,cyano, hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄alkylamino or di-C₁₋₄-alkylamino; comprising conversion of a compound ofFormula VIII

wherein Z is halogen, to a compound of Formula VII.
 12. The method ofclaim 11, wherein the compound of Formula VII is obtained by: i)reacting the compound of Formula VIII

wherein Z is halogen, with Mg or an organolithium compound, or with anorganometallic complex composed of Mg and/or Mn and/or Li and alkyl oraryl groups to achieve a first intermediate; ii) subsequently reactingsaid first intermediate with CO₂, CS₂ or a compound of Formula IX

wherein A and X are independently selected from halide, CN, OR⁵ or SR⁶where R⁵ and R⁶ are independently selected from C₁₋₆alkyl, aryl,heteroaryl or benzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl orbenzyl groups are unsubstituted or substituted with halogen, C₁₋₄ alkyl,cyano, hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄alkylamino or di-C₁₋₄ alkylamino, NR⁷R⁸ where R⁷ and R⁸ areindependently selected from hydrogen, C₁₋₆ alkyl, aryl, heteroaryl orbenzyl and each of these C₁₋₆ alkyl, aryl, heteroaryl or benzyl groupsare unsubstituted or substituted with halogen, C₁₋₄ alkyl, cyano,hydroxy, C₁₋₄ alkoxy, trifluoromethyl, nitro, amino, C₁₋₄ alkylamino ordi-C₁₋₄ alkylamino; Y is O, S, or NR⁹ where R⁹ is selected fromhydrogen, C₁₋₆ alkyl, aryl, heteroaryl or benzyl and each of these C₁₋₆alkyl, aryl, heteroaryl or benzyl groups are unsubstituted orsubstituted with halogen, C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkoxy,trifluoromethyl, nitro, amino, C₁₋₄ alkylamino or di-C₁₋₄ alkylamino; toachieve the compound of Formula VII.
 13. Citalopram as the base or anyconvenient salt thereof manufactured by the methods of claims 1 and 8.14. A pharmaceutical composition comprising citalopram as the base orany convenient salt thereof according to claim 13.